As a group, RNA viruses represent an enormous public health problem in the U.S. and worldwide. Well-known RNA viruses include influenza virus (including the avian and swine isolates; also referred to herein as flu), Hepatitis C virus (HCV), Dengue virus (DNV), West Nile virus (WNV), SARS-coronavirus (SARS), MERS-coronavirus (MERS), respiratory syncytial virus (RSV), and human immunodeficiency virus (HIV). These viruses are responsible for pandemic outbreaks and threats to public health that have occurred throughout history. Flaviviruses, Henipaviruses, Filoviruses, and Arenaviruses are among emerging RNA viruses that pose significant public health and biodefense threats. These viruses collectively place hundreds of millions of people at risk of infection throughout the world. Many of the emerging RNA viruses cause viral hemorrhagic fever and can result in significant morbidity and mortality. Dengue virus (DNV) and West Nile virus (WNV) are both Flaviviruses (positive strand RNA virus) and Arboviruses, transmitted through mosquitoes; thus these viruses represent a potent potential biological threat through their ability to transmit readily among insects or animals and humans, high infectivity, and their potential to be weaponized in bioterror events.
At least 4 subtypes of Ebola virus (EV) are infectious to humans (Zaire, Sudan, Bundibugyo, and Cote d'lvoire). EV outbreaks have been described in Africa with a fatality rate of up to 90%. Feldmann, H., et al. (2011) Lancet 49, 1-14. Cases of EV infection have been reported in other countries including, very recently, the United States. The natural host for EV is not defined, but nonhuman primates (NHP) are susceptible. EV is a negative-strand RNA virus of the Filoviridae and can be spread effectively from person-to-person.
Seasonal flu infects 5-20% of the population annually, resulting in 200,000 hospitalizations and 36,000 deaths. Influenza can precipitate viral or secondary bacterial pneumonia, and complicated disease in those at the extremes of age or with weakened immune systems. Coronaviruses are common throughout the world and typically cause mild to moderate respiratory illness, although certain coronaviruses cause severe respiratory illness and death. A 2003 multi-country outbreak of SARS-coronavirus infection resulted in approximately 8,000 infections and nearly 800 deaths. Recently there have been reported cases of Middle East Respiratory Syndrome caused by MERS-coronavirus.
More than 170 million people worldwide are infected by HCV, and 130 million of these are chronic carriers at risk of developing chronic liver diseases (cirrhosis, carcinoma, and liver failure). As such, HCV is responsible for two thirds of all liver transplants in the developed world. Recent studies show that the death rate from HCV infection is rising due to the increasing age of chronically infected patients.
DNV is the most prevalent flavivirus in humans, is endemic in most tropical and subtropical countries, and is currently emerging elsewhere including the U.S. and across the Pacific Islands. DNV circulates as 4 serotypes (DNV1-4) and following a first infection, re-infection can lead to fatal hemorrhagic fever and shock syndrome. Infection is believed to provide life-long immunity against reinfection by the same serotype, but not against other serotypes. Epidemic outbreaks have been reported in many countries throughout Latin America, South-East Asia, and the Western Pacific Regions. It is estimated that between 50 and 100 million cases of Dengue fever occur globally each year. Dengue Hemorrhagic Fever and Dengue Shock Syndrome represent severe forms of the disease. Currently there is no specific antiviral therapy to treat DNV infection and no approved vaccine.
WNV is a related flavivirus that is endemic in regions of Africa and Asia, but is now emerging in the Western hemisphere. WNV is neuroinvasive to cause serious encephalitis disease and is lethal in about 6% of cases. Neuroinvasive WNV can present as meningitis, encephalitis or less frequently a flaccid paralysis referred to as poliomyelitis. WNV was largely absent from North America prior to 1999, but reemerged on the continent following an isolated outbreak of encephalitis in New York. In the subsequent 7 years, WNV infection spread throughout the 48 contiguous United States, and current estimates suggest as many as 2-3 million Americans have been infected. Over the past 20 years, outbreaks have been reported in parts of Europe, North Africa, the Middle East, and North America. Currently there is no specific antiviral therapy to treat WNV infection and no approved vaccine.
Among the RNA viruses listed, very few vaccines are currently approved for clinical use. One such vaccine exists for influenza virus, which must be revised and administered annually. Accordingly, drug therapy is essential to mitigate the significant morbidity and mortality associated with these viruses. Unfortunately, the number of antiviral drugs is limited, many are poorly effective, and nearly all are plagued by the rapid evolution of viral resistance and a limited spectrum of action. Ribavirin, a guanine nucleoside analog, has been studied in clinical trials of diverse RNA virus infections and is likely the most broadly acting antiviral agent available. Ribavirin is approved to treat Hepatitis C virus (HCV) and respiratory syncytial virus (RSV) infection, and Lassa virus related mortality was shown to be reduced with intravenous ribavirin treatment. However, it is weakly effective as a single agent and has significant hematologic toxicity. Both classes of acute influenza antivirals, adamantanes and neuraminidase inhibitors, are only effective within the first 48 hours after infection, thereby limiting the window of opportunity for treatment. High resistance to adamantanes already restricts their use, and massive stockpiling of neuraminidase inhibitors will eventually lead to overuse and the emergence of resistant strains of influenza.
Based on the foregoing, there is an immense and unmet need for effective treatments against viral infections. Most drug development efforts against viruses target viral proteins. RNA viruses have small genomes, with many encoding less than a dozen proteins, resulting in a very limited number of viral targets for new drugs. This is a large part of the reason that current drugs are narrow in spectrum and subject to the emergence of viral resistance. However, there is benefit to discovery of new viral targets for inhibition. Alternatively, direct-acting antiviral therapy can work to counteract any infection mechanisms such as viral entry into a host cell.
New antiviral therapy can act directly against viruses. In particular, new antiviral therapy can exploit the fact that these viruses are susceptible to control by innate intracellular immune defenses that function to suppress virus replication and spread. Compounds that act on cellular targets are likely to be more effective, be less susceptible to the emergence of viral resistance, cause fewer side effects, and be effective against a range of different viruses. An effective broad-spectrum antiviral, whether used on its own or in combination with other therapies, would be an enormous benefit to current clinical practice. While interferon is in principal host-mediated and broad spectrum, many viruses have evolved the ability to disrupt interferon signaling downstream of drug action at the receptor. An important criterion is the development of drugs that activate innate immune signaling below specific virus countermeasures and are a unique addition to conventional antiviral compounds in development or on the market. As one such innate immune antiviral response, the RIG-I-like receptor (RLR) pathway of innate antiviral immunity can impose a potent blockade to RNA virus infection through the actions of a variety of antiviral defense genes.